Photochemical preparation of a bicyclic lactone

ABSTRACT

Synthesis of cis 2-(1&#39;&#39;-methyl-2&#39;&#39;-isopropenylcyclobutyl)ethanol, a component of the boll weevil sex attractant, and intermediates therefor, in which 5-hydroxy-pent-2-ynoic acid ester or ethers thereof is methylated followed by cyclization to yield 3methylpent-2-eno-5-lactone which is irradiated in presence of ethylene to yield 2,3-cycloethylene-3-methylpentano-5-lactone which is cleaved and converted into 2-(1&#39;&#39;-methyl-2&#39;&#39;isopropenylcyclobutyl)ethanol.

Unite States atent lnventor John B. Siddal Palo Alto, Calif. Appl. No.883,301 Filed Dec. 8, 1969 Patented Dec. 14, 1971 Assignee ZoeconCorporation Palo Alto, Calif.

PHOTOCHEMICAL PREPARATION OF A BICYCLIC LACTONE 6 Claims, No DrawingsUS. Cl 204/162 R, 260/343 Int. Cl B0lj l/l0 Field of Search 260/343;

References Cited OTHER REFERENCES Chapman, Organic Photochemistry, Vol.l (1967) pages 307 & 309.

Primary Examiner-Howard S. Williams Attorney-Donald W. EricksonABSTRACT: Synthesis of cis 2-( l '-methyl-2'-isopropenyl'-cyclobutyhethanol, a component of the boll weevil sex attractant, andintermediates therefor, in which S-hydroxy-pent-Z- ynoic acid ester orethers thereof is methylated followed by cyclization to yield3-methylpent-Z-en0-5-lactone which is irradiated in presence of ethyleneto yield 2,3-cycloethylene-3- methylpentano-S-lactone which is cleavedand converted into 2-( l '-methyl-2 '-isopropenylcyclobutyl)ethanol.

PHOTOCHEMICAL PREPARATION OF A BICYCLIC LACTONE The present inventionrelates to the synthesis of cis 2-(imethyi-Z'-isopropenylcyclobutyl)ethanol, one of three essentialcomponents of the male boll weevils sex attractant, and intermediatestherefor. The components of the male boll weevils sex attractant havebeen reported at Chemical & Engineering News, 36-38, Apr. 28, 1969 andScience 166, lOlO, Nov. 21, 1969.

it is an object of the present invention to provide a synthesis for thepreparation of cis 2-( l '-methyl-2'-isopropenylcyclobutyl)ethanol andkey intermediates therefor which uses readily available startingmaterials and is economical to practice. Other objects and advantageswill become apparent as the invention is hereinafter described indetail.

In the practice of the invention, there is first prepared the lactoneill (3-methylpent-Z-eno-S-lactone) which is outlined as follows:

In the above formulas, R represents hydrogen or an acid labile group,such as tetrahydropyran-Z-yl, tetrahydrofuran-Zyl, t-butyl, and thelike, and R represents lower alkyl, cycloalkyl, aralkyl or aryl.

The lactone (lll), a key intermediate, in accordance with the presentinvention is prepared by first methylating the acetylenic ester (1) andthen converting the intermediate (ll) into the lactone (lll).Advantageously, the process can be carried out in one reaction vessel.Methylation of S-hydroxypent-Z-ynoic acid ester (1) or the ether thereofis accomplished by treatment with dimethylcopper lithium in an organicsolvent inert to the reaction. There is used at least one molarequivalent of dimethylcopper lithium or a slight excess. The preparationof the dimethylcopper lithium reagent is carried out at low temperaturesof the order of about room temperature to about l50 C., preferably fromabout C. to about -l00 C. in an organic solvent medium inert to thereaction, such as ethers, hydrocarbons, and the like, e.g., pentane,ether, tetrahydrofuran, monoglyme, toluene, diglyme and dioxane; andmixtures thereof, such as etherzpentane, ether:hexane, and the like.instead of isolating the dimethylcopper lithium reagent, it ispreferable to add the acetylenic ester (1) to the prepared solution ofthe reagent while maintaining a low temperature and preferably underinert atmosphere, such as argon or nitrogen. The reaction is complete ina matter of minutes to a few hours depending primarily on the solventmedium. The intermediate (II) is then, preferably without isolation,converted into the lactone (lll). To accomplish this conversion, theintermediate ester (II) is hydrolyzed to the free acid which is thencyclized to the lactone (III) by treatment with a proton donor, such asan inorganic acid or organic acid. Hydrolysis of the ester to the freeacid is accomplished by treatment with a base, such as an alkali metalhydroxide, alkali metal bicarbonate, alkali metal carbonate, or analkaline earth metal hydroxide, e.g. sodium hydroxide, potassiumhydroxide, sodium bicarbonate, barium hydroxide, potassium bicarbonate,sodium carbonate, potassium carbonate, and the like, preferably analkali metal. The base should be present in the amount of at least onemolar equivalent. The hydrolysis is usually conducted at about roomtemperature; although, lower or higher temperatures, such as reflux, maybe used depending on such factors as the nature of the ester moiety andbase employed. A suitable method is to add a solution of the base in alower alcohol, such as methanol or ethanol, upon completion of themethylation reaction. After hydrolysis of the ester is complete, thereaction mixture is then made acid by the addition of a proton donor andagitated. A proton donor, such as an inorganic or organic acid, such ashydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, aceticacid, p-toluenesulfonic acid, preferably dilute aqueous acid, such asaqueous hydrochloric acid or aqueous sulfuric acid. If the hydroxylgroup of the acetylenic ester (1) bears an ether group, the choice ofproton donor will depend upon the relative ease with which the ethergroup is removed. In the case of an intermediate of formula ll wherein Ris t-butyl, it is not necessary to treat the intermediate with base tohydrolyze the ester. In this case, hydrolysis of the t-butyl ester,removal of labile ether group R, if present, and cyclization can beaccomplished by treatment with a proton donor alone. In this method, itis preferably to use a strong acid, such as hydrochloric acid,perchloric acid, p-toluenesulfonic acid, trifluoroacetic acid, sulfuricacid, and the like. Depending upon such factors as the miscibility ofthe acid with the solvent medium of the previous step and the acid used,the acid may be added as a aqueous solution, with or without organicsolvent carrier or in concentrated form without dilution. The acidtreatment is generally done at room temperature with stirring, althoughlower or higher temperatures, such as 0 C. to reflux, may be beneficialdepending on such factors as the particular acid used, solvent mediumand the time within which it is desired to complete the reactions. Forexample, in the case of trifluoroacetic acid, it is preferable to workat about 0 C. The lactone can be used as the crude product or purifiedby distillation prior to irradiation with ethylene.

Methylation of the acetylenic ester (1) in accordance with the presentinvention can also be accomplished using methyl copper or a complexformed from the reaction of cuprous salt with methylmagnesium halide,i.e. bromide, chloride, or iodide. Cuprous salt, such as cuprous iodide,cuprous bromide, cuprous chloride, cuprous acetate or cuprous cyanide isgenerally used. Methyl copper is prepared using equimolar amounts of acuprous salt, such as cuprous iodide, and methyl lithium. Similarly, thecomplex formed from cuprous salt and methyl-magnesium halide is preparedusing equimolar amounts. in such instance and particularly in the caseof methyl copper, it is advantageous to employ a solubilizing ligand,such as tertiary phosphine, tertiary phosphite, secondary amine ortertiary amine to improve the organic solvent solubility and reactivityof the reagent. Suitable ligands include tri-n-butyl phosphine,triethylphosphite, pyrrolidine, piperadine, trimethylphosphine,diethylamine, and the like. The ligand should be present in the amountof at least 1 molar equivalent based on the cuprous salt employed in thereaction mixture; however, in the case of the complex formed fromcuprous salt and methylmagnesium halide, 2 molar equivalents of theligand should be employed. Preparation of the methylation reagent isaccomplished using the conditions and procedure described hereinabovefor the preparation of dimethylcopper lithium.

The lactone (Ill) is then treated with ethylene under photochemicaladdition conditions to yield the 2,3-cycloethylene-3-methylpentano-S-Iactone (IV).

Photochemical addition of ethylene to the lactone (ll!) is accomplishedby irradiating a solution of the lactone (Ill) in an organic solventinert to the reaction which is saturated with ethylene. Suitable inertorganic solvents include ethers, alcohols, halogenated hydrocarbons andhydrocarbons, such as ether, tetrahydrofuran, benzene, hexane,cyclohexane. Depending upon the concentration of the reaction solution,temperature, solvent and light source, the reaction is complete within afew minutes to several hours. Suitable sources of light include sunlightand electric light means, such as conventional fluorescent light,mercury are light, and the like. The effective wavelength appears to bein the UV range of from about 200 mu. to about 400 mu. Filters, such asPyrex and quartz, may be used in conjunction with sensitizers, such asacetophenone, benzophenone, and the like. The photochemical addition canbe carried out at room temperature, although higher and lowertemperatures can be employed, generally temperatures below roomtemperature are used. The concentration of the lactone (III) in thesolvent medium should always be considerably less than the concentrationof ethylene, generally less than percent.

The lactone (lV) is then cleaved and converted into cis (1'-metl1yl-2'-isopropenylcyclobutyl)ethanol according to the followingoutlined procedure.

In the practice of the above process, the lactone (IV) is reacted withmethyl lithium in ether to yield the diol (V) which is treated withacetic anhydride with heat to yield the acetate (VI). Hydrolysis of theacetate using alkali metal hydroxide, or the like, in alcohol affordsthe desired alcohol (VII).

The compounds of formula I wherein R is an acid labile group, such astetrahydropyran-2 yl, tetrahydrofuran-Z-yl or t-butyl, can be preparedby standard procedures. Tetrahydropyran-2-yl ether andtetrahydrofuran-Z-yl ether can be prepared by treating the hydroxylcompound with dihydropyran and dihydrofuran, respectively, in thepresence of hydrochloric acid. The t-butyl ether can be prepared bytreating the hydroxyl compound with isobutene in the presence ofsulfuric acid.

The term lower alkyl, as used herein, refers to an alltyi group of oneto six carbon atoms, straight and branched chain, such as methyl, ethyl,n-propyl and t-butyl. The term cycloalltyl," as used herein, refers to acycloalkyl group of four to eight carbon atoms. The term arall yl, asused herein, refers to an aralkyl group of up to carbon atoms, such asphenyl, naphthyl, tolyl, ethylphenyl and t-butylphenyl. Suitableprocedures for preparation of acetylenic acid esters are set forth at CA40:7157 (1946); CA 41:705 (1947); R. A. Raphael, Acetylcnic Compounds inOrganic Synthesis," Butterworth & Co., London (1955); and A. W. Johnson,The Chemistry of the Acetylenic Compounds, Vol. II, London (1950).

The following examples are provided to illustrate the present invention.Temperature in degrees Centigrade.

EXAMPLE 1 To a mixture of 950 mg. of cuprous iodide in 10 ml. of drytetrahydrofuran is added at 20 in an argon atmosphere, 5.9 ml. ofa 1.67M ethereal methyl lithium solution.

To the above prepared solution is added a solution of 550 mg. of methyl5 hydroxypent-Z-ynoate in 2 ml. of tetrahydrofuran. After about 2 hours,1 ml. of water is added and the mixture allowed to rise to roomtemperature. To the mixture is added 2 equivalents of aqueous sodiumhydroxide in methanol and the mixture stirred at room temperature untilthe ester disappears (about 26 hours). Then, there is added aqueoushydrochloric acid with stirring until the mixture is acidic. Whencyclization is complete, as followed by thin-layer chromatography, themixture is saturated with brine and then extracted with ether. The etherextracts are washed with brine and water and dried over sodium sulfate.The solvent is evaporated under reduced pressure to yield3-methylpent-2- eno-S-lactone (Ill) which can be purified bydistillation.

EXAMPLE 2 A solution of l g. of 3methylpent-2-eno-5lactone in 50 g. ofbenzene is saturated with ethylene. The solution, while continuing tointroduce ethylene, is irradiated using a mediumpressure mercury vaporlamp (450 watts) with Pyrex filter for about 4 hours. Then the reactionmixture is evaporated under reduced pressure to yield2,3-cycloethylene-3methylpentano- 5lactone (IV) which can be purified bydistillation.

EXAMPLE 3 To a solution of l g. of 2,3-cycloethylene-3-methylpentano-5-lactone in ether is added 2 molar equivalents of methyl lithium inether with stirring at about 0. The mixture is stirred for about 60minutes and allowed to rise to room temperature. The mixture is dilutedwith aqueous ammonium chloride and water and separated. The organicphase is washed with water, dried over sodium sulfate and evaporatedunder reduced pressure to yield the diol (V) which can be purified bydistillation.

A mixture of l g. of the diol (V) and 5 ml. of acetic anhydride isheated at reflux for about 2 hours. The mixture is cooled and dilutedwith saturated NaCl water and then ether. The organic phase is washedwith brine and water, dried over sodium sulfate and evaporated underreduced pressure to yield the acetate (Vll).

A mixture of l g. of the acetate (VI) and 0.1 g. of potassium hydroxidein methanol is stirred for about 2.5 hours. The mixture is diluted withwater and then ether. The organic phase is washed with water, dried oversodium sulfate and evaporated to yield the monohydric alcohol (VII)which can be purified by distillation.

EXAMPLE 4 A mixture of 0.5 moles of S-hydroxypent-Z-ynoic acid, 2.0moles of isobutylene, about 0.3 ml. of concentrated sulfuric acid and 50ml. of methylene chloride is stirred at l0 to 0 for about 24 hours. Thecold reaction mixture is poured into cold dilute aqueous sodiumbicarbonate with stirring and separated. The organic phase is washedwith water, dried over magnesium sulfate and solvent removed underreduced pressure to yield t-butyl-St-butoxypent-Z-ynoate.

To a mixture of 950 mg. of cuprous iodide in ml. of dry tetrahydrofuranis added at -20 in an argon atmosphere, 5.9 ml. ofa 1.67 M etherealmethyl lithium solution.

To the above-prepared solution is added at 78 a solution of 560 mg. oft-butyl-St-butoxypent-Z-ynoate in 20 ml. of tetrahydrofuran. After about2 hours, I ml. of water is added and the mixture allowed to rise to roomtemperature. To the mixture is added aqueous perchloric acid untilacidic. The mixture is then refluxed until cyclization is complete asfollowed by thin-layer chromatography. The cooled mixture is dilutedwith brine and then extracted with ether. The ether extracts are washedwith brine and water, dried over sodium sulfate and solvent removed byevaporation. The residue is distilled to yield3-methylpent-Z-eno-S-lactone (ill).

EXAMPLE 5 To a mixture of 950 mg. of cuprous iodide and l molarequivalent of pyrrolidine in 50 ml. of dry ether is added at 50 in argonatmosphere 2.95 ml. of a 1.67 molar ethereal methyl lithium solution.

After about 30 minutes, there is added 550 mg. of methyl 5-(tetrahydropyran-Z'-yloxy)pent-2-ynoate in 20 ml. of ether at 78 withstirring. After about 1 hour, I ml. of water is added and the mixtureallowed to rise to room temperature. To the mixture is added 1.5equivalents of aqueous potassium hydroxide in methanol and the mixturestirred at room temperature until the ester disappears. The mixture isthen made acidic by the addition of p-toluenesulfonic acid and stirredwith heating until cyclization complete as followed by thinlayerchromatography. The reaction mixture is then worked up as described inexample i to yield the lactone (Ill),

EXAMPLE 6 This example illustrates hydrolysis of the ester by generationof the base in situ.

To a mixture of 950 mg. of cuprous iodide in ml. of dry tetrahydrofuranis added at in an argon atmosphere, 5.9 ml. ofa 1.67 M ethereal methyllithium solution.

To the above-prepared solution is added a solution of 550 mg. of methyl5-hydroxypent-2-ynoate in 2 ml. of tetrahydrofuran. After about twohours. 1 ml. of water is added and the mixture allowed to rise to roomtemperature. 4 ml. of ethyl alcohol is added and the mixture stirred atroom temperature. After about 10 hours, there is added aqueoushydrochloric acid with stirring until the mixture is acidic. Whencyclization is complete, as followed by thin-layer chromatography, themixture is saturated with brine and then extracted with ether. The etherextracts are washed with brine and water and dried over sodium sulfate.The solvent is evaporated under reduced pressure to yield3-methylpent-2- eno-5-lactone (III) which is purified by distillation.

The above process is repeated with the exception that instead of adding1 ml. of water and allowing the mixture to rise to room temperature, 4ml. of ethanol is added directly and then stirring at room temperatureto yield the lactone (ill).

The procedure of this example illustrates the generation of base insitu, i.e., lithium hydroxide, which advantageously eliminates theaddition of base as a separate step. Similarly, magnesium hydroxide canbe generated in situ when using the methylating reagent formed from thereaction of cuprous salt and methylmagnesium halide.

What is claimed is:

l. A process for the preparation of a bicyclic lactone of the formula:

C Ha

which comprises the methylation of an acetylenic acid ester of theformula:

CHa-OR GET and irradiating a solution of the monocyclic lactone in anorganic solvent inert to the reaction saturated with ethylene to yieldsaid bicyclic lactone.

2. The process according to claim 1 wherein R is hydrogen and R is loweralkyl.

3. The process according to claim 2 wherein R is methyl.

4. The process according to claim 1 wherein R is tetrahydropyran-Z-yland R is lower alkyl.

5. The process according to claim 4 wherein R is methyl.

6. The process according to claim 1 wherein the acetylenic ester ismethyl S-hydroxypent-Z-ynoate, the methylating reagent is dimethylcopperlithium, the base is aqueous sodium hydroxide and said cyclization isaccomplished using aqueous inorganic acid.

2. The process according to claim 1 wherein R is hydrogen and R'' islower alkyl.
 3. The process according to claim 2 wherein R'' is methyl.4. The process according to claim 1 wherein R is Tetrahydropyran-2-yland R'' is lower alkyl.
 5. The process according to claim 4 wherein R''is methyl.
 6. The process according to claim 1 wherein the acetylenicester is methyl 5-hydroxypent-2-ynoate, the methylating reagent isdimethylcopper lithium, the base is aqueous sodium hydroxide and saidcyclization is accomplished using aqueous inorganic acid.